The overarching goals of this project are to better understand the temporal relation of cardiac autonomic function to cognitive decline and incident mild cognitive impairment (MCI) and to explore whether mechanistic pathways involving remediable risk factors underlie these associations. Given the lack of effective treatments for Alzheimer's disease, there is an urgent need to identify methods for early identification of individuals at high risk for developing of the disease. Prior evidence has linked cardiac autonomic function to health outcomes, and there is increasing interest in better understanding the role of the autonomic nervous system in cognitive function. Heart rate variability (HRV), the beat to beat variation in heart rate that results from modulation of sinus node activity by the autonomic nervous system, has emerged as a feasible, non-invasive means of quantifying cardiac autonomic control in clinical and population based research settings. Although cardiac autonomic dysfunction has been correlated with Alzheimer's disease and mild cognitive impairment, prospective studies have not established whether low HRV predicts cognitive decline and incident mild cognitive impairment. We propose novel ambulatory measurement techniques for assessing heart rate variability in a naturalistic, real world setting. Using measures from the other components of this Program Project, we will link HRV indices prospectively with both clinic based and novel ambulatory cognitive assessments. We extend our current work regarding the role of vascular function in cognitive decline to examine whether HRV is mechanistically linked to cognition via vascular or inflammatory processes. We will use the trans ?cranial Doppler ultrasound measures of cerebral vascular hemodynamics that were introduced in the current project, along with MRI measures of white matter integrity to examine potential vascular mechanisms. We propose new measures of pro- and anti-inflammatory markers to explore potential inflammatory pathways. This will be the first large cohort study to examine whether HRV is a predictor of cognitive decline and incident cognitive impairment and to explore mechanistic pathways. Achieving the overall project goals will answer important questions regarding the utility of HRV for identifying individuals at risk for subsequent cognitive impairment, and regarding targets for risk factor modification.